Based on previous classical epidemiological and family studies there is a significant polygenic contribution to the etiology of lymphoma. The study design required to define the relevant genes contributing to this risk is the case-control association study. Using this study design, we plan to test the hypothesis that genetic variation within a number of pathways important in the development and function of the immune system affect the risk of developing lymphoma. By carrying out a study such as this, we will be able to define important genetic mechanisms in the etiology of lymphoma and associations described will also yield clues to important environmental factors. In particular we will evaluate the role of genetic polymorphisms in two large case-control studies that form part of the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). One study based here in the U.S. comprised of at least 400 cases and 800 controls, and another study based in Leeds, England, consists of 800 cases and 800 controls. We have already extracted DNA and there is extensive epidemiological information for both study populations. One defined advantage of these current studies is the use of the REAL classification system, which allows the definition of distinct clinico-pathological subgroups of NHL, which have varying molecular characteristics. The data from each study will be analyzed separately then pooled together and eventually combined with data obtained from ongoing analyses being carried out at the NCI from a number of other studies of NHL with similar design. In this manner, we will investigate the relationship between functional polymorphisms in key candidate genes / pathways and their effect on the risk of developing NHL. Candidate genes for analysis have been selected using a hypothesis- and pathway-driven approach developed in collaboration with an international group of investigators. Functional polymorphisms in key genes involved in acquired and innate immunity, folate metabolism, energy homeostasis, xenobiotic metabolism, and oxidative stress will be analyzed primarily using high-throughput Taqman-based allelic discrimination techniques. These analyses will constitute one of the largest NHL molecular epidemiology studies to date. Using a multi-study approach will provide sufficient power to carry out multivariate analyses to detect interactions between genetic and environmental factors and NHL risk that will provide a paradigm for future international collaborative studies of rare diseases.